Ibogaine is a drug found in the roots of Tabernanthe iboga, a shrub from Gabon, in equatorial west central Africa. Ibogaine has been known since the 1800's as an agent which at low doses has psychostimulant properties, and at high doses can induce a hallucinatory (oneirophrenic) state. For this reason it has been used in the Gabonese society for initiation ceremonial rites.
Ibogaine has also been used as an adjunctive agent in psychotherapy and psychoanalysis, and more recently has been described as an agent that may be able to suppress symptoms of dependence or withdrawal from addictive drugs. Discovery of this property of ibogaine led to the issuance of a number of U.S. patents to Howard S. Lotsof, including U.S. Pat. No. 4,499,096 (issued in 1985, concerning heroin addiction), U.S. Pat. No. 4,587,243 (issued in 1986, concerning cocaine and amphetamine abuse), U.S. Pat. No. 4,857,523 (issued in 1989, concerning alcohol abuse), U.S. Pat. No. 5,026,697 (issued in 1991, concerning tobacco and nicotine), and U.S. Pat. No. 5,152,994 (issued in 1992, concerning people suffering from multiple drug dependencies).
Lotsof's assertions regarding the usefulness of ibogaine in reducing various types of drug dependencies are consistent with evidence generated in several studies on laboratory animals. For example, in rats, ibogaine reduces morphine self-administration and ameliorates symptoms associated with morphine withdrawal and decreases preference for cocaine consumption; see, e.g., Glick et al 1991, Glick et al 1992, Sershen et al 1992, Cappendijk and Dzoljic 1993, and Sershen et al 1994 (full citations to articles are provided below).
Additional information on various cellular mechanisms involved in ibogaine's activity are provided in Deecher et al 1992, Sershen et al 1992, Glick et al 1993, and Popik et al 1994. For example, it appears that ibogaine inhibits binding to a dopamine transporter site (Sershen et al 1992), to a kappa opioid receptor site (Deecher et al 1992), to a voltage-dependent sodium channel site (Deecher et al 1992), and to an NMDA glutamate receptor ion channel site (Popik et al 1994). It is not clear what functional significance these findings may have, because the studies were conducted using receptor binding assays, and a serious limitation of such assays is that they shed no light on whether an agent acts as an agonist or antagonist, or, indeed, whether its binding activity might produce a mixture of agonist and antagonist effects which cancel out to yield no net effect on receptor function.
The recent report by Popik et al (1994) that ibogaine inhibits binding to an NMDA receptor ion channel site is of special interest in relation to the potential of ibogaine for counteracting drug dependencies. Although the evidence from the Popik et al receptor binding study does not clarify what type of action it may have at the NMDA subtype of glutamate receptor, it has been reported recently that agents which are known antagonists of NMDA receptors can prevent the development of tolerance to opiate analgesics (see Marek et al 1991; Trujillo and Akil 1991; Ben-Eliyahu et al 1992; Tal and Bennett 1993), to benzodiazepine anxiolytics such as diazepam (sold under the trade name VALIUM; Turski et al, PCT patent application WO 94/01094), to cocaine (Pudiak and Bozarth 1993), and to alcohol (Wu et al 1993). Accordingly, it was postulated in Popik et al 1994 that the action of ibogaine in blocking drug tolerance, craving, and dependence may signify that it acts as an antagonist at NMDA receptors.
The Applicant has conducted recent experiments using functional bioassay techniques demonstrating unequivocally that ibogaine does act as an antagonist at NMDA receptors, and that it also acts as an antagonist at sigma receptors. Both of these discoveries are important aspects of this invention, and have not been previously reported.
In addition, the present invention pertains, not to blocking drug addiction mechanisms, but to an entirely separate and distinct use for ibogaine, which involves the reduction or prevention of brain damage caused by ischemia (inadequate blood flow to the brain, as occurs during stroke, cardiac arrest, and trauma), hypoxia (inadequate oxygen supply to the brain, as occurs during suffocation, drowning, carbon monoxide poisoning, etc.), and certain other types of crises or conditions. These crises or conditions generate a process in the central nervous system (CNS) known as "excitotoxicity". Since this subject is complex, additional information is provided below on excitotoxicity, on the role of glutamate as an essential neurotransmitter under healthy conditions and as a deadly neurotoxin under certain abnormal conditions, and on the roles of NMDA receptors and NMDA antagonist drugs under such conditions. This is a brief overview; additional information on these topics is provided in numerous articles and books, including Choi 1988 and Olney 1989 (review articles) and in the multi-volume treatise on the central nervous system edited by Adelman (either the 1987 or the 1995 edition).
Additional newly-developed information on the neuronal circuitry described herein is provided in a co-pending U.S. patent application, Ser. No. 08/381,334, co-invented by the same Applicant herein, entitled "USE OF ALPHA-2 ADRENERGIC DRUGS TO PREVENT ADVERSE EFFECTS OF NMDA RECEPTOR HYPOFUNCTION". The contents of that application are incorporated herein by reference; if that co-pending application has not yet issued as a patent, then it will be opened for public inspection and copying upon issuance of a patent based upon this instant application.
The Glutamate Neurotransmitter System
Glutamate (Glu) is recognized as the predominant excitatory neurotransmitter (messenger molecule) in the mammalian central nervous system (CNS); for a review, see the chapter by Olney entitled "Glutamate" in The Encyclopedia of Neuroscience, edited by Adelman (either the 1987 or the 1995 edition).
Glu is involved in transmitting messages from one nerve cell (neuron) to another in many different circuits within the CNS, and therefore serves many important functions. Glu mediates these functions by being released from a sending neuron onto a receptor at a synapse on the surface of a receiving neuron. A synapse is a signal-transmitting junction between two neurons. Binding of Glu to the synaptic receptor initiates signal transfer by opening an ion channel and triggering ionic currents. This is considered an excitatory process, because it stimulates an increased level of electrochemical activity in the receiving neuron.
NMDA and non-NMDA Subtypes of Glutamate Receptors
There are several different subtypes of receptors through which Glu transmits messages. A particularly important receptor through which Glu mediates a wide range of functions is the N-methyl-D-aspartate (NMDA) receptor, which is so called because NMDA, a molecule structurally related to Glu, is highly selective and potent in activating this receptor (reviewed by Watkins 1987 and Olney 1989). Other major classes of Glu receptors are kainic acid receptors and Quis/AMPA receptors; these two classes are often referred to collectively as non-NMDA receptors. Both NMDA and non-NMDA receptors are normally activated by Glu and are ordinarily referred to as Glu receptors although they are also activated to a lesser extent by aspartate, a related excitatory amino acid. Glu receptors are also sometimes referred to generically as excitatory amino acid (EAA) receptors.
Antagonist Drugs that Block NMDA Receptors
As will be described below, antagonist drugs that block Glu receptors offer great promise as therapeutic agents. Therefore, drug companies have recently begun developing drugs that block glutamate receptors. Initially, the major emphasis was on developing drugs that block NMDA receptors and two broad classes of such compounds are now available. One class is referred to as competitive NMDA antagonists; these agents bind at the NMDA/GLU binding site (such drugs include CPP, DCPP-ene, CGP 40116, CGP 37849, CGS 19755, NPC 12626, NPC 17742, D-AP5, D-AP7, CGP 39551, CGP-43487, MDL-100,452, LY-274614, LY-233536, and LY233053). Another class is referred to as non-competitive NMDA antagonists; these agents bind at other sites in the NMDA receptor complex (such drugs include phencyclidine, dizocilpine, ketamine, tiletamine, CNS 1102, dextromethorphan, memantine, kynurenic acid, CNQX, DNQX, 6,7-DCQX, 6,7-DCHQC, R(+)-HA-966, 7-chloro-kynurenic acid, 5,7-DCKA, 5-iodo-7-chloro-kynurenic acid, MDL-28,469, MDL-100,748, MDL-29,951, L-689,560, L-687,414, ACPC, ACPCM, ACPCE, arcaine, diethylenetriamine, 1,10-diaminodecane, 1,12-diaminododecane, ifenprodil, and SL-82.0715). For reviews, citations, and chemical structures, see, e.g., Rogawski 1992 and Massieu et al 1993, and articles cited therein.
Toxic Effects of Excessive Glu Activity; Utility of NMDA Antagonist Drugs
In addition to its many beneficial functions, the Glu molecule harbors treacherous neurotoxic potential. Glu neurotoxicity is referred to as "excitotoxicity" because the neurotoxic action of Glu, like its beneficial actions, is mediated by an excitatory process (reviewed by Olney 1990 and Choi 1992). Ordinarily, when Glu is released at a synaptic receptor, it binds only transiently to the receptor then is rapidly removed from the receptor region by a transport process that transports Glu back inside a cell. Under certain abnormal conditions, including stroke, epilepsy and CNS trauma, the Glu uptake process fails and Glu accumulates at the receptor and persistently excites electrochemical activity until it literally excites to death neurons that have Glu receptors. Since almost all of the neurons in the CNS have Glu receptors, this mechanism can trigger an enormous amount of CNS damage.
As used herein, the term "acute CNS injury" includes ischemic events (which involve inadequate blood flow, such as a stroke or cardiac arrest), hypoxic events (involving inadequate oxygen supply, such as drowning, asphyxiation, or carbon monoxide poisoning), trauma to the brain or spinal cord, certain types of food poisoning which involve an excitotoxic poison such as domoic acid, and seizure-mediated neuronal degeneration, which can result from persistent epileptic seizure activity (status epilepticus). A large body of evidence has implicated the NMDA receptor as one receptor subtype through which Glu mediates a substantial amount of CNS injury, and it is well established that NMDA antagonists are effective in protecting CNS neurons against excitotoxic degeneration in these acute CNS injury syndromes (reviewed by Choi 1988 and Olney 1990).
CNS trauma represents a special situation in which excessive activity at NMDA receptors can cause neuronal damage by both a direct and indirect mechanism. Persistent activation of NMDA receptors can directly excite neurons to death but, in addition, the hyperexcitation process involves excessive influx of charged ions into CNS cells which creates an osmotic imbalance that causes abnormal amounts of water to flow in with the ions, the net result being excessive swelling of millions of CNS cells and increased intracranial pressure (because the bony cranial vault is inflexible and cannot expand to accommodate the increased volume of the swollen cells). Elevated intracranial pressure represents an indirect mechanism that contributes significantly to both morbidity and mortality in CNS trauma victims, and NMDA antagonists are useful not only in preventing direct excitotoxic damage but in reducing increased intracranial pressure and thereby preventing indirect damage.
In addition to neuronal damage caused by acute insults, excessive activation of Glu receptors may also contribute to more gradual neurodegenerative processes leading to cell death in various chronic neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), AIDS dementia, Parkinson's disease and Huntington's chorea (Olney 1990). It is considered likely that NMDA antagonists will prove useful in the therapeutic management of such chronic diseases.
Toxic Effects of Excessive Glu Activity; Utility of non-NMDA Antagonist Drugs
The toxic effects of excessive Glu activity have been described in detail above. As mentioned above, when agents that selectively block non-NMDA Glu receptors became available, they were tested for efficacy in protecting against ischemic neuronal degeneration in several animal ischemia models and were found to be at least as effective and in some cases more effective than NMDA antagonists. The non-NMDA antagonist NBQX has also been shown to be effective in preventing neuronal degeneration associated with brain trauma. Non-NMDA antagonists that penetrate blood CNS barriers have not been available for a long enough time to allow them to be tested for neuroprotective efficacy against all types of neuropathological conditions involving excessive Glu activity. However, it is considered likely that they will be found effective in many such conditions, because many neurons in the CNS have both NMDA and non-NMDA receptors and therefore are vulnerable to excitotoxic degeneration mediated through either class of receptor whenever excessive Glu comes in contact with such receptors.
NMDA Antagonist Drugs: Both Beneficial and Detrimental
As described above under the heading, "Utility of NMDA Antagonist Drugs", NMDA antagonists can have several important beneficial effects. However, despite these beneficial effects, NMDA antagonists can also cause serious detrimental side effects which manifest as neurotoxic changes in CNS neurons and as psychotomimetic symptoms (described in the immediately following paragraph). As described in Olney et al 1989b, and in U.S. Pat. No. 5,034,400 (Olney 1991), the neurotoxic changes include the formation of vacuoles and dissolution of mitochondria in large neurons in the posterior cingulate and retrosplenial (PC/RS) regions of the cerebral cortex of adult rats. These changes are detected histologically within 2 to 4 hours following a single subcutaneous treatment with either competitive or non-competitive NMDA antagonists (Olney et al 1991). Twenty four hours after NMDA antagonist treatment, the vacuolar changes are diminished but new changes in the form of abnormal expression of heat shock protein (HSP) appear and the HSP changes remain detectable for up to 2 weeks after NMDA antagonist treatment. While all of the above changes occur following treatment with a relatively low dose of an NMDA antagonist, higher doses have been shown to kill neurons not only in the PC/RS cortex but in several other neocortical and limbic brain regions (Corso et al 1994; Fix et al 1993). In addition, it has been shown that subchronic treatment with daily injections of an NMDA antagonist for 3-5 days causes neuronal cell death in the PC/RS and other cortical and limbic brain regions (Corso et al 1992; Ellison and Switzer 1993; Horvath and Buzsaki 1993). It has been shown that both competitive and non-competitive NMDA antagonists cause both the vacuolar reaction and death of cerebrocortical neurons.
In addition to these neurotoxic changes in neurons of the adult rat brain, NMDA antagonists are known to cause psychotomimetic effects in adult humans (reviewed by McCarthy 1981). These psychotomimetic effects were first observed many years ago in patients treated with phencyclidine, a drug that was introduced into human medicine as an anesthetic in the late 1950s. This was long before it was known that phencyclidine acts as an NMDA antagonist, in fact long before NMDA receptors were first described. In this early period, phencyclidine was introduced as an anesthetic agent and it was found immediately that patients anesthetized with phencyclidine displayed psychotic symptoms (termed an "emergence reaction") when they were coming out from under the anesthesia. Because these psychotomimetic side effects were quite severe, phencyclidine was immediately withdrawn from use in clinical medicine. Subsequently, phencyclidine became well known as a widely abused illicit hallucinogenic street drug (angel dust, PCP).
In the 1980's it was discovered that the site of action of PCP in the CNS is at a "PCP recognition site" within the ion channel of the NMDA Glu receptor. At this site, PCP acts as a non-competitive antagonist that blocks the flow of ions through the NMDA ion channel. Thus, PCP and related agents such as ketamine and MK-801 that also act at the PCP site became known as non-competitive NMDA antagonists. Since ketamine, a drug currently used in human anesthesia, is known to cause "emergence reactions" similar to but not as severe as those caused by PCP, it became evident to researchers in the late 1980s that all drugs acting at the PCP site as non-competitive NMDA antagonists were likely to have psychotomimetic side effects. This caused pharmaceutical companies to shift their focus away from non-competitive agents acting at the PCP site to competitive NMDA antagonists acting at the NMDA recognition site. However, in the last few years three competitive NMDA antagonists (CPP, CPPene, CGS 19755) have been administered in relatively low doses to adult human subjects and all three of these agents induced a psychotomimetic reaction (Kristensen et al 1992; Herrling 1994; Grotta 1994). Therefore, it is now recognized that various competitive NMDA antagonists and various non-competitive NMDA antagonists all cause the same pathomorphological effects in rat brain (Olney et al 1991; Hargreaves et al 1993) and also have psychotomimetic effects in humans (Kristensen et al 1992; Herrling 1994; Grotta 1994). Thus, it seems likely that these two types of side effects are morphological and psychological manifestations of the same toxic process and that the ability of a given agent to produce these adverse effects does not depend on the site within the NMDA receptor channel complex where it binds, but on the efficacy with which it blocks the functional activity of this receptor channel complex. In practical terms, a major obstacle to the use of NMDA antagonists as neurotherapeutic drugs lies in their potential for inducing adverse CNS side effects, including both brain damage and psychosis.
Status of NMDA Receptor Antagonists as Neurotherapeutic Drugs
Despite the remarkable neuroprotective and other potential neurotherapeutic effects of NMDA antagonists, no agent in this category has gained approval from FDA for human clinical use, the major problem being that all agents in this class that have been tested thus far have been found to have the above-mentioned neurotoxic and psychotomimetic side effects. Therefore, FDA has either placed a moratorium on the further clinical testing of such compounds or has restricted clinical trials to an evaluation of exceedingly low doses which have very little chance of proving to be therapeutically effective.
Several types of drugs that can reduce or prevent the neurotoxic side effects of NMDA antagonists have been described (e.g., Olney et al 1991). However, there is a great deal of resistance in the pharmaceutical industry to the use of drug combinations because it is vastly more expensive to gather the requisite toxicological data to establish the safety of multiple drugs used in combination than to establish the safety of a single drug. Of equal importance is the fact that the chances are great that after millions of dollars are invested in demonstrating the safety of a drug combination in experimental animals, it will finally be found that humans cannot tolerate the combined side effects of such a complex medical regimen. Thus, progress in this important drug development area has come nearly to a standstill at the present time.
One potential resolution of the problem would be if a single molecule could be found that has potent NMDA antagonist properties without accompanying neurotoxic side effects. Progress toward development of such molecules has heretofore not been promising. In fact, every NMDA antagonist introduced into clinical trials thus far has been shown to produce severe psychotic reactions at relatively low doses. This immediately engenders the suspicion that these agents may also cause injury and/or death of cerebrocortical neurons in humans, as they have been shown to do in experimental animals.
The Present Invention
One object of the present invention is to disclose that ibogaine decidedly is an NMDA antagonist that is effective in preventing NMDA receptor-mediated excitotoxic neurodegeneration.
Another object of this invention is to disclose that ibogaine can be administered to rats at high doses (in excess of doses required to block NMDA receptors) without causing any histological evidence of neuronal injury or cell death.
Another object of this invention is to disclose that ibogaine exerts antagonist activity at a sigma receptor. In light of additional experimental data gathered by the Applicant, this explains its lack of neurotoxic side effects; the blocking action of ibogaine at sigma receptors serves to prevent the neurotoxic side effects of its NMDA antagonist activity. Thus, this invention discloses that ibogaine is a potentially very useful neurotherapeutic drug which incorporates, within a single molecule, both (1) effective neuroprotective action against acute excitotoxic neuronal injury, and (2) a safener mechanism that protects against its own neurotoxic side effects.
An additional object of the present invention is to disclose that ibogaine can be administered together with a second drug (such as a muscarinic or non-NMDA antagonists or alpha-2 adrenergic agonists) to prevent the hallucinogenic side effects of ibogaine, without suppressing the beneficial anti-excitotoxic NMDA antagonist activity of ibogaine.